This project uses DNA microarrays and a nonhuman primate infection model to explore the host response to influenza virus containing one or more of the genes from the 1918 pandemic strain. In specific aim 1, we intend to provide a nonhuman primate model in which to examine influenza virus pathogenesis. Nonhuman primates in the wild have antibody titers to human influenza A, and studies in which macaques were experimentally infected with influenza A/HongKong/156/97 have demonstrated that these animals match the human response and pathology to a great extent. In this aim, we will evaluate the clinical course, pathology, and gene expression patterns associated with influenza virus infection of pig-tailed macaques (Macaca nemestrina). We will begin these studies using the A/Texas/36/91 strain and an engineered version of this strain that contains the 1918 NS1 gene. Additional viruses will be evaluated as suggested by results obtained from the projects headed by Drs. Garcia-Sastre, Palese, and Basler (using cell culture and mouse models). In specific aim 2, we will use microarrays and state-of-the-art information technologies to profile changes in cellular gene expression in response to influenza virus infection. Studies on macaque lung tissues will be performed using commercial human DNA arrays and unique macaque DNA arrays that have been constructed by our laboratory. Gene expression profiling of macaque peripheral blood cells may also reveal signature genes whose expression patterns in response to infection by highly pathogenic viruses may form the basis of a rapid screening test for infection of human populations. Analyses will also be performed on human cell lines infected in vitro, and on lung tissues isolated from infected mice. Our goal is to analyze the effects on cellular gene expression mediated by specific viral gene products associated with the 1918 pandemic strain and to attempt to elucidate the mechanisms by which certain strains of influenza virus become highly pathogenic. Importantly, the results of these analyses are also likely to suggest new hypothesis-driven investigations to be explored by our collaborators. The use of genomic technologies and the expansion of nonhuman primate models for emerging infectious diseases are primary goals of the NIAID Strategic Plan for Biodefense Research, and the availability of a macaque infection model will provide a critical resource for studying the pathogenesis of influenza virus as well as therapeutic and vaccine strategies.